CZ297679B6 - Crystalline form B of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide - Google Patents

Abstract

In the present invention, there is described a stable crystalline form of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide. This crystal structure, designated Form B, is more stable, has favorable handling properties and is characterized by its melting point, X-ray and other physical characterizations. There is also described a process for preparing the above-indicated crystalline form and a pharmaceutical composition in which the form is comprised.

Description

(57)

A stable crystalline form of 4- [5-methyl-3-phenylisoxazol-4-yl] -benzenesulfonamide, Form B, having advantageous handling properties is disclosed. Also described is a process for its preparation and a pharmaceutical composition comprising it.

CO m

O) NCO σ> CM

N O

Crystalline Form B of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide

Technical field

The invention relates to the field of anti-inflammatory pharmaceuticals and in particular to crystalline Form B of 4 [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide, processes for preparing the crystalline form and pharmaceutical compositions.

BACKGROUND OF THE INVENTION

Prostaglandins play a major role in the inflammatory process and inhibition of prostaglandin production, in particular the production of PGG2, PGH2 and PGE2 are of common interest in the discovery of a new anti-inflammatory drug. However, conventional non-steroidal anti-inflammatory drugs (NSAIDs), which are active in alleviating the pain caused by prostaglandin and in edema associated with the inflammatory process, are also active in influencing other prostaglandin-regulated processes not associated with the inflammatory process. The use of high doses of the most common NSAIDs may therefore cause some side effects, including life-threatening ulcers, limiting their therapeutic effect. Alternatively, corticosteroids can be used in place of NSAIDs, which have more severe side effects, especially during long-term treatment.

Previous NSAIDs prevented the production of prostaglandins by inhibiting enzymes in the conversion of arachidonic acid / prostaglandin in humans, including the cyclooxygenase (COX) enzyme. The recent discovery of an inducible enzyme associated with inflammation (called "cyclooxygenase-2 (COX)" or "prostaglandin G / H synthase II") involves a variety of targeted inhibition that more effectively suppresses inflammation, fever, and has less severe side effects associated with inhibition cyclooxygenase1 (COX-1).

A group of substituted isoxazoles is disclosed in U.S. Patent No. 5,633,272 to Talley et al., And International Application WO 96/25405. The compounds are disclosed to be useful in the treatment of inflammation and inflammation-related disorders. 4- [5-Methyl-3-phenyl-isoxazol-4-yl] -benzenesulfonamide has an effect as a selective COX-2 inhibitor over COX-1.

For all pharmaceutical compounds and compositions, chemical and physical stability is important for the commercial development of this drug substance. This stability includes stability under ambient conditions, especially humidity and storage conditions. Increased stability under different storage conditions is necessary for resistance to various possible storage conditions during the life of a commercial product. Stable drug is not affected by special storage conditions or frequent inventory transfers. The drug compound must also be stable during the manufacturing process, which often requires grinding the drug to achieve particles of uniform size and surface. Unstable materials often undergo polymorphic changes. Any modification of the drug substance that enhances its stability is therefore a significant benefit for less stable substances.

It has been found that 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide can be prepared in various crystalline forms. The former (form "A") is unstable after mechanical comminution (grinding) and is also thermally unstable. Recently, a crystalline form (Form "B") has been established that is more stable and has better physical properties.

SUMMARY OF THE INVENTION

It has been found that 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide can be prepared in a crystalline form referred to as "Form B". Form B is characterized by the following methods.

- 1 CZ 297679 B6

Thaw

Melting points were determined using a Thomas Hover melting point apparatus or Mettler's FP900 thermosystem. Melting range was determined by differential scanning calorimetry on a TA Instruments differential scanning calorimeter (Model 2100 controller, Model 912 dual calorimeter). The sample (1-2 mg) was placed in an unsealed aluminum dish and heated at 10 ° C / minute.

Form A showed an onset of melting at 160.2 ° C with a stable exotherm at 170.9 ° C caused by crystalline rearrangement (see Figure 1). Form B showed an onset of melting at 170.9 ° C (peak at 172.5 ° C). An example of DCS Form B is shown in Figure 2.

Infrared spectroscopy

Infrared spectra were obtained using a Nicolet DRIFT (diffused reflectance infrared fourier transform) spectrophotometer. The Magna System 550 was used. The Spectra Collector System and a 3 mm sample container were used. Samples (2%) were analyzed in KBr and scanned from 400 to 4000 cm ^-1 . An example of the infrared absorption spectrum of Form B is shown in Figure 3b. The Y-axis represents the adjusted reflectance in Kubelka-Munk units.

The infrared spectrum of Form B is characterized by absorption at approximately 3377, 1170, 1151, 925, 844, 745, 729 and 534 cm ^-1 , which is different from the measured spectrum of Form A. The infrared spectrum of Form A is characterized in part by absorption at approximately 723 cm " ¹ , which differs from the measured absorption of the spectrum of Form B. The crystals of Form B of the invention preferably exhibit an infrared spectrum substantially the same as that shown in Fig. 3a.

Powder X-ray diffraction

The analysis was performed with a Siemens D5000 powder diffractometer. The original (raw) data were measured for 2Θ values from 2 to 50 in steps of 0.02 and every 2 seconds.

Table I shows the significant parameters of the 2Θ values and the intensities of the major peaks of Form B. An example of the X-ray diffractogram of Form A is shown in Figure 4. An example of the X-ray diffractogram of Form B is shown in Figure 5. 221, 15 447, 17 081, 19 798 and 23 861.

-2GB 297679 B6

Table I

Peak Angle 2Θ

Distance D Peak

I / Imax

No (deg)

Cps (%)

X

12.221 13.693 14.227 15.447 15.801 16, 678 17.081 18.165 19.066 19.400 19.798 20.578 22.008 22.540 22.975 23.580 23.861 24.553 25.206 25.560 25.940 26.200 27.295 28 _f 595 29.124 29.656

7,2361

6.4617

6.2203

5,7314

5.6039 5.3110 5.1868 4.8796 j6510

4,5717

4.4807 4.3126 4.0354 3.9414

3,8678 3,7699 3,7261 3,6226 3,5302 3,4822 3,4320 3,3985

3.2646

3.1191 3.0636 3.0099

502.38 38.03

51.46

599.94 793 79

239.95 331.31 270.21 73.16 200.13

789.23

209.43 691,33

71.87

137 j23

394.27

602.27

397.23

192.44

77.74

31.47

20.87 151,54

207.74

161.44 73.94

63.29

4.79 6.48 75.58 100.00

30.23 41.74 34.04

9.22

25.21 99.43 26.38 87.09

9.05

17.29 49.67 75 y 87 50.04

24.24

9.79 3.96 2.63 19.09 26.17 20.34 9.32

Form B can be prepared by recrystallization of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide from a suitable solvent. In the preparation of Form B, 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide is dissolved in the volume of the solvent and cooled until crystals are formed. The compound is preferably added to the solvent at a temperature of at least about 25 ° C. More preferably, the temperature of the solvent is between 30 ° C and the boiling point of the solvent. The temperature is preferably in the range of about 65 ° C to 75 ° C.

Optionally, a hot solvent is added to the compound and the mixture can be cooled until crystals are formed. Preferably the solvent has at least 25 ° C. The better solvent temperature is in the range of about 15 ° C to about 80 ° C. The temperature is preferably in the range of about 65-75 ° C.

Preferably, the compound is mixed with the solvent in an amount of about more than three times the weight of the compound. The better solvent to compound ratio is about 7 to 10 times.

Preferably, the solution is slowly cooled until crystallization of Form B. Preferably, the solution is cooled more slowly than 0.5 ° C / minute. The solution is preferably cooled at a rate of about 0.3 ° C / minute * or slower.

A suitable solvent is a solvent or solvent mixture that dissolves the compound and any impurity at elevated temperature but preferably upon cooling precipitates Form B. A suitable solvent is one of the alcohols, methyl-tert-butyl ether, methyl ethyl ketone and a combination of alcoholic solvents, methyl-zerc butyl ether, acetonitrile, water, acetone, tetrahydro furan and methyl ethyl ketone. Alcohol or aqueous alcohol is preferred. A more preferred solvent is selected from the group consisting of methanol, aqueous methanol, ethanol, aqueous ethanol, isopropyl alcohol and aqueous isopropyl alcohol. Aqueous methanol, methanol, ethanol 3A, aqueous ethanol and an isopropanol / methanol mixture are best.

Optionally, the compound is dissolved in one solvent and a co-solvent is added to promote crystallization of the desired form.

The formed Form B crystals are separated from the solvent by filtration or centrifugation. The crystals are preferably dried, preferably in a temperature range of about 30 ° C to about 100 ° C. The crystals are best dried under vacuum.

Form B may alternatively be prepared by heating Form A at a sufficient temperature to convert to Form B. Preferably, Form A is heated in a temperature range of about 50 ° C to 140 ° C.

4- [5-Methyl-3-phenylisoxazol-4-yl] benzenesulfonamide Form B is useful in the treatment of inflammation in a patient, thereby not limiting its effect and treating other disorders caused by cyclooxygenase-2, such as an analgesic in the treatment of pain and pain headache, or as an antipyretic in the treatment of fever. For example, Form B may be used in the treatment of arthritis, including, but not limited to, rheumatoid arthritis, spondyloarthropathy, gout arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Form B is useful in the treatment of asthma, bronchitis, menstrual pain, premature labor, tendinitis, bursitis, liver disease including hepatitis, skin diseases such as psoriasis, eczema, burns, dermatitis and post-operative inflammation, including inflammation associated with, for example, eye surgery cataract surgery and refractive surgery. Form B can also be used to treat digestive disorders such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis. Form B can be used to prevent and treat cancers such as colorectal and breast, lung, prostate, bladder, cervix and skin cancers. Form B is useful in the treatment of glaucoma, angiogenesis and retinopathy. Form B can be used to treat inflammation in such diseases, such as vascular diseases including atherosclerosis, migraine head region, periarteritis nodosa, thyroitis, aplastic anemia, Hodgkin's syndrome, scleroderma, rheumatoid fever, type I diabetes, neuromuscular diseases such as myasthenia gravis white matter diseases including multiple sclerosis, sarcoidosis, nephrotic syndrome, Bechterew's disease, polymyositis, gingivitis, nephritis, hypersensitivity, edema occurring after injury, ischemic heart disease and the like. Form B can also be used in the treatment of ocular diseases such as retinitis, conjunctivitis, retinopathy, uveitis, ocular photophobia, and acute ocular tissue damage. Form B can also be used to treat pulmonary inflammation, for example, associated with viral infections and cystic fibrosis. Form B can be used in the treatment of certain central nervous system disorders, such as cerebral cortex dementia, including Alzheimer's disease and central nervous system damage prior to stroke, ischemia, seizure and trauma. Form B is useful as an anti-inflammatory agent, for example in the treatment of arthritis with significantly less negative side effects. Form B can also be used in the treatment of allergic rhinitis, respiratory insufficiency syndrome, endotoxin shock syndrome, osteoporosis, and bone resorption disorders. Form B can also be used in the treatment of pain, including post-operative pain, dental pain, muscle pain, cancer-related pain, and others. Form B can be used in the prevention of cardiovascular disease, for example atherosclerosis, liver disease and dementia, for example Alzheimer's disease.

In addition to treating patients, this form is also useful in the veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More suitable animals include horses, dogs and cats.

Form B can also be used as adjunctive therapy to partially or completely replace other conventional anti-inflammatory drugs, such as steroids, NSAIDs, 5-lipooxygenase inhibitors, LTB4 receptor antagonists, and LTA4 hydrolysis inhibitors.

-4GB 297679 B6

Suitable LTA4 hydrolysis inhibitors include RP-64966, (S, S) -3-amino-4- (4-benzyloxyphenyl) -2-hydroxybutyric acid benzyl ester (Scripps Res. Inst.), N- (2 (R) - (cyclohexymethyl) -3 (hydroxycarbamoyl) propionyl) -L-alanine (Searle), 7- (4- (4-ureidobenzyl) phenyl) heptanoic acid - (Rhone-Poulenc Rorer) and lithium salt of 3- (3 (1 E, 3E-) tetradecadienyl) -2-oxiranyl) benzoic acid (Searle).

Suitable LTB4 receptor antagonists include, but are not limited to, ebselene, linazolast, ontazolast, Bayer Bay-x-1005, Ciba Geigy CGS-25019C, Leo Denmark compound ETH-615, MAFP compound, Terumo compound TMK-688, Tanabe compound T-0757, Lilly compound LY-213024, LYT-210073, LY223982, LY233469 and LY255283, LY-293111, 264086 and 292728, ONO compounds ONO-4057 and ONO-LB-448, Shionogi compound S-2474, calcitrol, Lilly compounds, Searle compounds SC -53228, SC-41930, SC-50605 and SC-51146, Wamer Lambert PBC 15, SmithKline Beecham SB-209247, and SK&F, SKF 104493. LTB4 receptor antagonists are preferably selected from the group consisting of calcitrol, ebselen, Bayer. Bay-x-1006, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615, Lilly compound LY-293111, ONO compound ONO-4057 and Terumo compound TMK-688.

Suitable 5-LO inhibitors include, but are not limited to, Abbott A-76745, 78773 and ABT761, Bayer Bay-x-1005, Cytomed CM1-392, Eisai E-3040, Scotia Pharmaceutica EF-40, Fujirebio F-1322, Merckle ML-3000 . Pardue Frederick PF-5901, 3M Pharmaceuticals R-840, rilopirox, flobufen, linasolast, lonapolene, masoprocol, ontasolast, tenidap, zileuton, pranlukast, tepoxalin, rilopirox, phlezelastine hydrochloride, enazadr phosphate and bunaprolast.

These forms can also be used in combination with opoids and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (for example, non-addictive) analgesics, monoamine elevation inhibitors, adenosine regulators, cannabinoid derivatives, substance P antagonists, neurokinin-1 receptor antagonists, sodium channel blockers and others. More preferred is a combination with compounds selected from the group consisting of morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, desocin, meptazinol, hydrocodone, oxycodone, methadone, Tramadol [(+) enantiomer], DuP 747, Dynorfm A, Enadoline 60180, HN-11608, E-2078, ICI-204448, acetominophen (paracetamol), propoxyphene, nalbuphine, RP-60180, HN-11608, E-2078, ICI-204448, acetominophen (paracetamol), propoxyphene, nalbuphine, E- 4018, filenadol, mirfentanil, amitriptyline, DuP 631, Tramadol [(-) enantiomer], GP-531, akadesin, AKI-1, AKI-2, GP-1683, GP-3269, 4030W92, tramadol racemate, Dynorphin A, E -2078, AXC 3742, SNX-111, ADL1294, IC-204448, CT-3, CP-99,994, and CP-99,994.

The invention includes pharmaceutical compositions comprising a therapeutically effective amount of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide in crystalline form B in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

Also within the scope of the invention is a class of pharmaceutical compositions comprising crystalline Form B in association with one or more non-toxic, pharmaceutically acceptable carriers and / or diluents and / or adjuvants (hereinafter generally referred to as "carriers") and optionally other active ingredients. Form B of the invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for a particular mode of administration and at a dose effective for the treatment. For example, the active form B and the composition may be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly, or locally.

For oral administration, the composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a certain amount of active ingredient. Examples of such dosage units are tablets or tablets

-5GB 297679 B6 capsules. The active ingredient may also be injected as a composition, for example, saline, dextrose or water, as a suitable carrier.

The amount of the therapeutically active compound to be administered and the dosage to treat the condition with the compound and / or composition of the invention depend on many factors including the age, weight, sex and medical condition of the patient, the severity of the disease, the mode and dosage regimen and compound, therefore, can vary widely. The pharmaceutical composition may contain the active ingredient in an amount of from about 0.1 to 2000 mg, preferably in the range of from about 0.5 to 500 mg, and most preferably from about 1 to 100 mg. A daily dose of from about 0.01 to 100 mg / kg body weight, preferably from about 0.5 to 20 kg / kg body weight, and most preferably from about 0.1 to 10 mg / kg body weight, may be suitable. The daily dose may be administered in one to four doses per day.

In the case of psoriasis and other skin diseases, it may be advantageous to apply a topical formulation of Form B to the affected area two to four times a day.

In inflammations of the eye or other external tissue, such as mouth and skin, the formulations are preferably applied in the form of a topical ointment or cream, or in the form of a suppository containing the active ingredients in a total amount of, for example, 0.075 to 30 wt. %, preferably 0.2 to 20 wt. % and most preferably 0.4 to 15 wt. %. In an ointment formulation, the active ingredients may be admixed with a paraffinic or water-miscible ointment base. The active ingredients may optionally be formulated in an oil-in-water cream. The aqueous phase of the cream base may also comprise, for example, 30 wt. % of a higher alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may optionally include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethylsulfoxide and similar analogs.

Form B may also be administered by the transdermal route. Advantageous topical application can also be achieved with a reservoir and porous membrane type patch or various solid forms.

In any case, the active agent is delivered continuously from the reservoir or microcapsules through the membrane to the active permeable adhesive agent that is in contact with the skin or mucosa of the recipient. When the active substance is absorbed through the skin, a controlled and predetermined flow of active substance to the recipient is applied. In the case of microcapsules, the encapsulant may also act as a membrane.

The oily phase of the emulsions of the invention may contain known ingredients as is customary. While the phase may contain only one emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil, or simultaneously with a fat and an oil. The hydrophilic emulsifier is preferably present together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both oil and fat. The emulsifier (s) with or without stabilizer (s) will form a so-called emulsifying wax, and the wax together with the oil and fat will form a so-called emulsifying base ointment which forms the dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate and others.

The choice of suitable oils and fats for the formulation is based on achieving the desired cosmetic properties since the solubility of the active compound in most oils used in pharmaceutical emulsion formulations is very low. Therefore, the cream should preferably not be a greasy, coloring and water-soluble product in a suitable consistency so as not to flow from tubes or other containers. Non-branched, branched chain, mono- or dibasic alkyl esters can be used, for example di-isoadipate, isocetyl stearate, diester of propylene glycol and coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or branched chain esters. These can be used alone or in combination depending on the conditions required. Alternatively, high melting point lipids can be used, for example white soft paraffin and / or liquid paraffin or other mineral oils.

-6GB 297679 B6

Formulations suitable for topical application to the eye also include eye drops where the active ingredients are dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredients. The anti-inflammatory active ingredients are preferably present in these formulations in a concentration of 0.5 to 20 wt. %, preferably 0.5 to 10 wt. %, and most preferably about 1.5 wt. %.

For therapeutic purposes, Form B is conventionally admixed with one or more adjuvants suitable for the mode of administration. For oral administration, the compound may be admixed additionally with lactose, sucrose, starch powder, cellulose esters or alkanoic acids, alkylcellulose esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium phosphoric and sulfuric salts, gelatin, gum arabic , sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then tableted or encapsulated for conventional application. These capsules or tablets may contain a sustained release formulation, which may be in the form of a dispersion of the active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules with one or more of the carriers or diluents mentioned for use in the formulations for oral administration. Crystalline Form B can be dissolved in water, polyethylene glycol, polypropylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. Other additives and methods of administration are well known in the pharmaceutical art.

Although the invention is described with respect to certain embodiments, the details of these embodiments are not intended to be limiting.

Description of the picture

Giant. 1 shows the differential scanning calorimetry (DSC) profile of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide Form A.

Giant. 2 shows the differential scanning calorimetry (DSC) profile of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide Form B.

Giant. 3a shows the infrared spectrum of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide Form B.

Giant. 3b shows the infrared spectrum of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide Form A.

Giant. 4 shows an X-ray diffractogram of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide Form A.

Giant. 5 shows an X-ray diffractogram of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide Form B.

DETAILED DESCRIPTION OF THE INVENTION

The following examples contain detailed descriptions of methods for preparing Form B. These detailed descriptions are within the scope of the invention and are given by way of example. These detailed descriptions are provided for illustrative purposes only and do not go beyond the scope of the invention. Unless otherwise indicated, all parts are by weight and temperature in degrees Celsius.

4- [5-Methyl-3-phenylisoxazol-4-yl] benzenesulfonamide was prepared by the following method, wherein ethanol 3 A is aqueous ethanol (5% water) denatured with methanol:

-7EN 297679 B6

Example 1

Step 1: preparation of deoxybenzoin oxime.

Sodium acetate trihydrate (152.5 g, 1.12 mol, 1.1 eq.) Was added to deoxybenzoin (200 g, 1.02 mol) and dissolved with ethanol (3A, 0.81) and water (0.24 L). ) in a 51 liter vessel with mechanical stirrer, reflux condenser and thermometer. The solution was stirred and heated to 70 ± 1 ° C. To hydroxylamine hydrochloride (78.0 g, 1.12 mol, 1.1 eq.) In a separate 500 mL flask was added water (0.1 L) with stirring. The hydroxylamine hydrochloride solution was added to the deoxybenzoin solution while maintaining the temperature of the reaction mixture at about 70 ° C. The mixture was heated to boiling (about 84 ° C) and held at this temperature for 40 minutes. The mixture was cooled to 40 ° C over two hours and water (10.5 L) was added to the reaction mixture. The reaction mixture was cooled to 20 ° C with stirring for an additional hour. Crystals of pure oxime were formed, which were isolated by filtration (Buchner funnel, Whatman No. 1 filter paper) under vacuum, washed with a mixture of 50 mL of ethanol 3A and 100 mL of water and water (1 L). The solid was dried for 2 hours under vacuum and after 12 hours at 55 ° C and vacuum was produced, pure deoxybenzoinoxime (213.2 g, 99%) was obtained.

Step 2. Preparation of 5-hydroxy-5-methyl-3,4-diphenylisoxazoline.

Deoxybenzoinoxime (Step 1) was dissolved in anhydrous THF (565 mL) under a nitrogen atmosphere. The solution was cooled to -20 ° C. The solution was treated with lithium diisopropylamide (2 M, 800 mL, 1.60 mol) and the reaction temperature was maintained at 10 ° C to 15 ° C. The reaction mixture was cooled to -10 ° C to 20 ° C and anhydrous ethyl acetate (218 mL) was added to the solution while allowing the reaction temperature to rise to a maximum of 25 ° C and held at 25 ° C for 30 minutes. The reaction mixture was cooled to approximately 0 ° C. Water was added to the cooling vessel to cool to 0 ° C to 5 ° C. The pre-cooled reaction mixture was transferred from the reaction vessel to the cooling vessel while maintaining the temperature of the cooling mixture below 25 ° C. The cooled mixture was cooled to 0-5 ° C. Hydrochloric acid (12M) was added to the mixture while maintaining the temperature at 25 ° C during the addition by controlling the rate of addition and stirring until all solids dissolved (approximately 5 minutes). The pH of the mixture was measured to be 3-4. The layers were separated and the organic layer was separated. Heptane was added to the organic layer while stirring. The organic layer was distilled until the temperature in the vessel reached 90 ° C - 91 ° C. The solution was cooled to 5 ° C and filtered. The solid was washed with 300 mL of ethyl acetate-heptane (20/80) cooled to 5 ° C. The solid product was dried under vacuum under nitrogen in a funnel for several hours at room temperature, and after two days isoxazoline was obtained (108.75 g, 57.7%).

Step 3. Preparation of 4 - [(5-methyl-3-phenyl) -4-isoxazolyl] benzenesulfonamide.

5-Hydroxy-5-methyl-3,4-diphenylisoxazoline (Step 2) (142 g, 0.56 mol) was dissolved in dichloromethane (568 mL) in a 31 L round bottom flask equipped with a heating mantle, mechanical stirrer, condenser cold water, a J-KEM temperature controller and a thermocouple to form a suspension. The suspension was stirred and cooled to <10 ° C. Chlorosulfonic acid (335 mL, 586.3 g, 5.04 mol) was added to the slurry and the vessel temperature was kept below 20 ° C by checking the addition. The mixture was heated to reflux (about 40 ° C), refluxed for 5 hours, and then cooled to 0 ° C to 5 ° C. The cooled reaction solution was slowly transferred to a 31-necked round bottom flask (mechanical stirrer and thermocouple) containing water (1000 mL), precooled to 0-5 ° C with vigorous stirring, and the vessel temperature was maintained below 10 ° C. The mixture was stirred for an additional 5 minutes. The layers were separated. In a separate 31 vessel (mechanical stirrer, external ice / salt bath, thermocouple), 28% ammonium hydroxide (700 mL) was cooled to 0-5 ° C. The dichloromethane solution was added to the stirred ammonium hydroxide solution and the temperature was kept below 10 ° C. The mixture was stirred at room temperature for 60 minutes. The resulting suspension was filtered and the solid washed with water (200 mL), dried, to give 4 - [(5-methyl-3-phenyl) -4-isoxazolyl] benzenesulfonamide as a white solid (94.3 g, 53.5%). .

-8EN 297679 B6

Step 4. Recrystallization of 4 - [(5-methyl-3-phenyl) -4-isoxazolyl] benzenesulfonamide.

The 4 - [(5-methyl-3-phenyl) -4-isoxazolyl] benzenesulfonamide from step 3 was dissolved in 300 mL boiling methyl ethyl ketone (2-butanone) and diluted with 10% aqueous isopropyl alcohol (300 mL, 270 mL anhydrous isopropyl alcohol and 30 mL). ml of water). The material was cooled to room temperature to form crystals. The crystals were isolated by filtration and dried in a vacuum drying oven (10 mm Hg), 100 ° C to give pure Form B (112.95 g, 65%): mp 172 ° C - 173 ° C.

Example 2

5-Methyl-3-phenyl-isoxazol-4-yl] -benzenesulfonamide (Example 1.3 step) (3 g) was mixed with 80% ethanol 3A / 20% water (9 mL) and heated to dissolve the solid. The vessel was cooled with an attached water bath and a precipitate formed in 1 hour. The solid was filtered off and washed with ethanol 3A. The material was dried under vacuum to dry residue (50 ° C - 60 ° C, 20 mm Hg). The resulting substance was identified as Form B.

Example 3

5-Methyl-3-phenylisoxazol-4-yl] benzenesulfonamide (Example 1.3 step) (10 g) was mixed with ethanol 3A (100 mL) and heated to dissolve the solid (about 70 ° C). The vessel was cooled to 20-25 ° C over 1.5 hours and a precipitate formed within 30 minutes. The solid was filtered off (Whatman No. 1 filter paper) and washed with water. The material was dried under vacuum to a dry residue (90 ° C, 50-100 mm Hg). The resulting substance was identified as Form B.

Example 4

5-Methyl-3-phenylisoxazol-1-yl] benzenesulfonamide (Example 1, Step 3) (9.8 g) was mixed with methanol (73.5 mL) and water (24.5 mL) and heated to 65 ° C to 70 ° C. The solution was allowed to stand for 10 minutes and then filtered while still hot to remove particulate matter. The solution was slowly cooled to 50 ° C (about 0.3 ° C / minute) and held at 50 ° C for 1 hour (during which time crystallization occurred). The solution was further cooled to 5 ° C (about 0.3 ° C / minute) and held at 5 ° C for 1 hour. The product was isolated by filtration and washed with 10 mL of cooled methanol / water (75/25). The product was dried at 95-100 ° C for 4 hours to obtain 8.55 g of Form B.

Example 5

To 5-Methyl-3-phenylisoxazol-4-yl] benzenesulfonamide (Example 1, Step 3) (25 g) was added methanol / isopropanol (80/20, 120 mL) (73.5 mL) and water (24 mL). (5 ml) and the solution was heated to approximately 68 ° C. After 15 minutes, the solution was still hot filtered through a glass filter funnel to remove particulate matter. The solution was then slowly cooled to 5 ° C (about 0.3 ° C / minute) over 3.3 hours and held at 5 ° C for 2 hours. The product was isolated by filtration and washed with 10 mL of cooled methanol / isopropanol (80/20). The product was dried at 95-100 ° C for 3 hours to give 11 g of Form B.

-9EN 297679 B6

Comparative Example 6

5-Methyl-3-phenylisoxazol-4-yl] benzenesulfonamide (Example 1.3 step) (10 g) was mixed with 20 mL of water: methanol (25:75) and heated until dissolved solid. The vessel containing the solution was placed on ice and the mixture was rapidly cooled to <10 ° C without crystallization. Several crystals were formed at the bottom of the vessel and crystallization rapidly occurred. After 10 minutes of standing, the solid was filtered and washed with 75% aqueous methanol. The material was evaporated to dryness under vacuum with water / nitrogen venting (50 ° C - 60 ° C, 20 Hg). The resulting substance was identified as Form A.

PATENT CLAIMS

Claims (8)

Crystalline Form B of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide with IR IR spectrum having the following peaks: 1170, 925, 844 and 729 cm ^-1 . Crystalline form B according to claim 1 having an IR spectrum without a distinct peak at 723 cm ^-1 . Crystalline Form B according to claim 1 having a melting point of 170.9 ° C and a peak at 172.5 ° C as determined by differential scanning calorimetry. 4. Crystalline Form B of 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide with an X-ray diffractogram with the following peaks: 12.221, 15.447, 15.801, 17.081, 19.798, 22.008, 23.580, 23.861 and 24.553, 15.447, 17.081, 19.798 and 23.861 degrees 2 0. A pharmaceutical composition comprising a therapeutically effective amount of crystalline Form B of 4- [5-methyl-3-phenylisoxazol-1-yl] benzenesulfonamide according to claim 1 or 4 together with at least one pharmaceutically acceptable carrier, excipient or diluent. A process for preparing crystals according to claim 1 or 4 comprising dissolving 4- [5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide in an alcohol-based solvent system to form a solution and then slowly cooling it. The process of claim 6, wherein the solvent system comprises one or more solvents selected from the group of methanol, isopropanol, aqueous methanol, and aqueous ethanol. 8. The process of claim 7 wherein the crystals are recrystallized from a mixture of isopropanol and methanol. 5 drawings -10US 297679 B6 CO Giant. 1 - 11 GB 297679 B6 Fig.2 - 12GB 297679 B6 Kubeiko Munk units Kubeiko Munk units 0.70.6-i 0.5 cm (cm-1) 0.6 i Fig. 3A 0.4: 03: inlet (cm-1) Giant. 3B - 13GB 297679 B6 2-Theta-scale 1008.00